The present invention relates to the field of hydrophilic coatings which are applied to medical devices, especially devices intended to be implanted, temporarily or permanently, in the body.
Among the many advances in medical practice in recent years is the development of medical devices that supplement the surgeon""s skills. Examples of these are a variety of vascular catheters and guide wires that can be used to treat remote areas of the circulatory system otherwise available only by major surgery. Another is the stent, a device that retards restenosis after angioplasty. Another is the intra-ocular lens that restores youthful eyesight to the elderly afflicted with cataracts. Heart valves, artificial pacemakers, and orthopedic implants are among a lengthening list.
Nearly all of the above-described devices are constructed of plastics and metals that were never intended to invade, and sometimes reside for prolonged periods, in the human body. They present surfaces that bear little or no semblance to those of the human organs, which are generally hydrophilic, slippery, and obviously biocompatible. The penalty imposed on invasive devices that are not biocompatible is that they tend to be treated as foreign objects by the body""s immune system. Inflammation and thrombosis often result.
Equally important for devices that must be inserted and moved through body tissues is their lubricity. Most metals and plastics have poor lubricity against body tissues, which results in mechanical abrasion and discomfort when the device is passed over the tissue.
The surface of devices already designed and manufactured from such materials can be made biocompatible, as well as hydrophilic and slippery, by properly designed coatings. Thus, the way has been opened to construct medical devices from conventional plastics and metals having the particular physical properties required, and then to apply suitable coatings to impart the desired properties to their surfaces.
Polysaccharides have been shown to be useful in making hydrophilic, lubricious coatings on substrates. Such coatings are described in U.S. Pat. Nos. 4,801,475, 5,023,114, and 5,037,677, the disclosures of which are hereby incorporated by reference. In general, these patents disclose bilaminar coatings comprising a primary coat that adheres tightly to a plastic substrate, and a top-coat which comprises a polysaccharide which is hydrophilic, lubricious and durable. The primary coat is sometimes called a xe2x80x9ctie-coatxe2x80x9d because it ties the top-coat to the substrate; it is also known as a base coat. Both of the terms xe2x80x9ctie-coatxe2x80x9d and xe2x80x9cbase coatxe2x80x9d are considered equivalent in this specification.
In the coatings described in the above-cited patents, the primary coat and the top-coat are grafted together with covalent bonds, and retain their individual identities even after grafting. These bilaminar coatings can be used on catheters, guide wires, prosthetic devices, intra-ocular lenses, or other devices which are permanently or temporarily inserted into the body.
It is a common feature of the coatings described above that organic solvents are needed at one stage or another of the process for applying the coating to the device. Many problems are associated with the use of those solvents. Virtually any organic solvent is toxic to a degree, and with many such solvents, the level of toxicity is high. The manifestations of this toxicity may include carcinogenic or teratogenic character, sensitization, and, at best, disagreeable odor. These characteristics can make the processing dangerous and unpleasant to the point of being intolerable. A survey of the patent literature discloses the use, in the manufacture of medical devices, of acetonitrile (toxic lachrymator), dimethylformamide (carcinogen), and N-methylpyrrolidinone (strong irritant, possible teratogen), for example. Another problem with the use of organic solvents is their flammability, which imposes the need for extra precautions to be taken during the manufacturing process.
Not only are these solvents a hazard in the workplace, but they also cause a problem due to the need to remove them completely after the manufacturing is completed. Polymers are well known to be highly retentive of traces of solvents even after exhaustive attempts to remove them. The possible threat to health, caused by exposing the patient""s blood stream even to traces of toxic solvents, is a factor to give concern to the conscientious manufacturer.
It is clearly important to eliminate the need for all solvents except pure water, in applying the desired surface characteristics to medical devices. Film-forming aqueous emulsions might satisfy the requirements. As a class, such materials have been known for more than fifty years as vehicles for leather coatings, interior and exterior paints, etc. Commercial products of this kind are generally described by their suppliers as xe2x80x9cacrylic latexxe2x80x9d or xe2x80x9cwater-based vehiclesxe2x80x9d, or even xe2x80x9clatex selected from the group consisting of isoprene and styrenexe2x80x9d, but the actual chemical compositions and the detailed formulations are proprietary information that is not disclosed. For the formulator of coatings for medical devices to be inserted into the human blood stream, this lack of assurance about the presence or absence of biologically harmful components in the products should be cause for concern.
Obviously, these industrial aqueous products were not developed specifically for use on medical devices only, or else such suitability would have been disclosed. Nevertheless, coatings for guide wires and catheters formulated with such products as major components have been patented, and perhaps used with human patients. See, for example, U.S. Pat. Nos. 5,756,144, 5,272,012, and 5,776,611, the disclosures of which are incorporated by reference herein. Furthermore, apart from the safety factor, these polymer compositions were designed and selected to comply with performance specifications for other commercial uses and were not known to be most appropriate in design for application as coatings on medical devices.
It has been found that a suitable coating can be prepared by selecting particular acrylic monomers, out of the large number available, for use in preparing emulsion polymers. Also, the choice of the proportions in which these monomers are used turns out to be a surprisingly critical factor in meeting the special requirements of medical devices.
The present invention comprises a substrate, typically a device intended to be implanted temporarily or permanently in the human body, having a bilaminar coating. The bilaminar coating includes a base coat which is firmly adhered to the substrate, and a top-coat which is chemically grafted to the base coat.
In the present invention, the base coat comprises an aqueous acrylic emulsion polymer. The polymer comprises a combination of one or more monomers having alkyl groups. The Equivalent Alkyl Number (EAN) of the polymer is defined by   EAN  =                              n          1                ⁢                  N          1                    +                        n          2                ⁢                  N          2                    +      …      +                        n          m                ⁢                  N          m                                    N        1            +              N        2            +      …      +              N        m            
where ni is a number of carbon atoms in an alkyl group of monomer i, and Ni is a number of moles of monomer i in the polymer, and where m is a positive integer. The EAN of the polymer used in the base coat of the present invention is in a range of about 3.5 to about 4.5. For the special case in which the polymer contains only one such monomer (i.e. m=1), the EAN must be 4, and the polymer comprises a butyl group.
The base coat and/or top-coat also contain functional groups which enable the two coats to be chemically grafted to each other. Preferably, the emulsion polymer of the base coat has a minimum film-forming temperature that is less than the temperature at which the coats are dried and cured.
An important feature of the present invention is that no organic solvents are used during the preparation of the coated substrate. Therefore, there can be no organic solvent in the final product. There is thus no need for a solvent-extraction step, after the coated substrate has been prepared, and the hazards arising from organic solvents in the finished product are entirely avoided.
The top-coat of the present invention is a hydrophilic polymer such as a polysaccharide, which is reinforced with a hydrophilic vinyl polymer capable of being crosslinked, such as polyacrylic acid or a water-soluble copolymer of acrylic acid, such as a copolymer of acrylamide and acrylic acid.
The present invention therefore has the primary object of providing a biocompatible coating for a medical device.
The invention has the further object of providing a coating as described above, wherein the coating is made without any organic solvents.
The invention has the further object of providing a coating as described above, wherein the coating is lubricious, highly durable, water resistant, and abrasion resistant.
The invention has the further object of improving the safety of coatings for medical devices, by eliminating the danger associated with residual amounts of organic solvents.
The reader skilled in the art will recognize other objects and advantages of the present invention, from a reading of the following detailed description of the invention, and the appended claims.
The requirements for any coating intended for use on medical devices, whether water-borne or in organic solvent, will be set forth and explained first. The specification will then show how the present invention fulfills these requirements.
The coating of the present invention must have the following properties:
(1) The product must be able, on drying, to form a continuous, adherent film of good integrity on the surface of the material to be coated. This means that the minimum film-forming temperature of the emulsion must be lower than the expected drying temperature to be used by the device fabricator.
(2) The formed polymer film must be flexible and adherent enough to conform without rupture to the bending and twisting of the coated device under the expected conditions of use.
(3) When the coated device is immersed for long periods in aqueous media such as human blood, the film must not be weakened or lose its integrity.
(4) The coating must present a hydrophilic, biocompatible surface and be firmly and securely bound to itself and to the substrate so that no fragments or harmful extract can contaminate an aqueous medium such as human blood.
A coating which satisfies the above requirements is made as described below.
The coatings of the present invention have two chemical characteristics, namely 1) the chemical composition of the acrylic copolymer (the xe2x80x9cbase coatxe2x80x9d) to be used in coating the substrate, and 2) the composition of the top-coat, which generates a lubricious and biocompatible external surface on the composite coating. These characteristics are discussed in order, below.
1. Monomer Proportions of the Base Coat
The principal monomers used to form the base coat of the present invention are acrylic in nature, e.g. alkyl acrylates and methacrylates. To specify these more exactly, it is necessary to define the term xe2x80x9cEquivalent Alkyl Numberxe2x80x9d (EAN). As used in this specification, the Equivalent Alkyl Number is the weighted average number of carbon atoms in the alkyl groups forming the copolymer molecule used in the present invention. More specifically, for a copolymer made from m monomers having various alkyl groups, and where n1 is the number of carbon atoms in the alkyl group of monomer-1, n2 is the number of carbon atoms in the alkyl group of monomer-2, etc., and where N1 is the number of moles of monomer-1, N2 is the number of moles of monomer-2, etc., the Equivalent Alkyl Number is defined as:                     EAN        =                                                            n                1                            ⁢                              N                1                                      +                                          n                2                            ⁢                              N                2                                      +            …            +                                          n                m                            ⁢                              N                m                                                                        N              1                        +                          N              2                        +            …            +                          N              m                                                          (        1        )            
In the special case where there is only one alkyl group, the EAN is the same as the integer n which defines the alkyl group, which is CnH2n+1.
The remarkable and surprising discovery of the present invention is that the preferred value of the EAN, for emulsion polymers made from acrylic monomers, is in the range of about 3.5-4.5. If only one alkyl group is present, the EAN must be exactly 4, because the number of carbon atoms must be an integer, and 4 is the only integer within the above-mentioned interval. Thus, in the special case where only one alkyl group is present, the alkyl group is the butyl group.
Moreover, it has been found that the isomeric forms of the alkyl groups are immaterial. For example, in the special case where there is only one alkyl group, namely the butyl group (C4H9), the butyl compounds can be normal-butyl, iso-butyl, or tertiary-butyl. The significance of the latter statement, in the context of the present invention, is that performance of the coating depends not on the steric configuration of the alkyl groups, but simply on the Equivalent Alkyl Number of the polymer or copolymer.
The definition of EAN contemplates that there will be combinations of different alkyl groups in the copolymer used to make the coating. According to the present invention, the preferred range of the EAN is from 3.5 to 4.5, and the latter values of EAN may be attained with many different combinations of alkyl groups. For example, the combination of one mol of lauryl acrylate and 2.67 mols of methyl methacrylate has, according to the equation defining EAN, an EAN of 4, i.e. an EAN equivalent to that of a butyl group. Similarly, a combination of one mol of octyl acrylate and 1.33 mols of methyl methacrylate also represents an average equivalent to the EAN of a butyl group. In another example, a combination of one mol of 2-ethylhexyl acrylate and 2 mols of ethyl methacrylate would also represent an average EAN equivalent to that of a butyl group. Thus, any of the above examples, as well as many other such combinations, qualify equally well for use in the present invention, with regard to the value of the EAN, i.e. the average size of the alkyl group.
As an example of the calculation of the mol ratios of components of a proposed copolymer used in the present invention, suppose that one wished to use a combination of ethyl acrylate and octyl methacrylate, and that one wanted the copolymer to have an EAN of four. First, choose one of the monomers as the reference monomer, say, the octyl methacrylate. We call the latter monomer N1, and give it the value of one mol. Since the alkyl group (octyl) in octyl methacrylate has eight carbon atoms, and since the alkyl group (ethyl) in ethyl acrylate has two carbon atoms, and setting EAN=4, Equation (1) becomes:                     (                  8          xc3x97          1                )            +              2        ⁢                  N          2                            1      +              N        2              =  4
so that N2=2. Thus, the monomers should be used in the mol-ratio of 1:2 octyl methacrylate to ethyl acrylate.
In a more general case, one can elect to use more than two monomers in proportions that will make the EAN fall within the desired range. For example, if one chose to use ethyl acrylate, amyl acrylate, and octyl methacrylate, with an EAN of 4, the calculations could be made as follows:
First, choose one of the given monomers as a reference monomer, say, octyl methacrylate. The latter will be monomer-1, and N1, by definition, is one. Let ethyl acrylate be monomer-2, and let amyl acrylate be monomer-3. There are 8 carbon atoms in the alkyl group (octyl) in octyl methacrylate, 2 carbon atoms in the alkyl group (ethyl) in ethyl acrylate, and 5 carbon atoms in the alkyl group in amyl acrylate. Substituting into Equation (1) yields:                     (                  8          xc3x97          1                )            +              2        ⁢                  N          2                    +              5        ⁢                  N          3                            1      +              N        2            +              N        3              =  4
Solving the latter equation gives
N3=2N2-4 
The latter is an equation of a straight line which could be plotted. Using the latter equation, one can select any of an infinite number of proportions of the three monomers which will satisfy the requirement that EAN=4. One such combination, for example, might be 3 mols of ethyl acrylate, 2 mols of amyl acrylate, and one mol of octyl methacrylate. Note that, since N1 was defined as one, the values of N2 and N3 indicate the number of mols of the given monomer per mol of the reference monomer.
The present invention does not exclude the possibility that minor amounts (less than about 10 mole percent) of other monomers may also be included in the base coat. For example, minor amounts of styrene, vinyl acetate, or N-vinylpyrrolidinone can enhance flow and leveling on particular substrates. Or, small amounts of specialty monomers well known in the art can be added to enhance adhesion to difficult surfaces. The EAN requirement, set forth above, would apply to the acrylic monomers component, independently of any such incremental addition of other monomers. The fundamental and governing characteristics associated with the required EAN will not be significantly affected by such addition.
A second requirement of the base coat composition of the present invention is that it display carboxyl, 1,2-epoxy, or other functional groups with a frequency sufficient to cause crosslinking of the copolymer when desired and to cause the copolymer to become grafted to the selected hydrophilic top-coat. Such functional groups are preferably one or more acidic monomers. The mole percentage of such functional monomer should be as low as will serve the purpose, because such groups can have the undesirable effect of increasing water sensitivity and consequent weakness of the coating. In any case, the mole percentage of acidic monomer will most desirably be in the range of 3 to 11 mole percent of the total monomer composition.
The acid functionality will be introduced by conjoint use of acrylic acid, methacrylic acid, itaconic acid, acryloxypropionic acid, or any other acidic monomer capable of copolymerization with the monomers selected as described above.
In addition to the monomer proportions in the emulsion copolymer discussed above, it is desirable that the minimum film-forming temperature (MFT) be lower than the temperature at which the coating will be dried and cured. The MFT and the glass temperature (Tg) are closely related, though not identical, and Tg can be calculated by a well-known method. In brief, the glass temperature indicates the transition In mechanical properties that occurs more or less sharply when a plastic material is heated and becomes softer, more flexible, and rubbery. The glass temperature of copolymers can be calculated from the known glass temperatures of the homopolymers, which have been determined experimentally, by use of the relationship known as the Fox equation:       1    Tg    =                    M        1                    tg        1              +                  M        2                    tg        2              +                  M        3                    tg        3              +    …  
where Tg is the glass temperature (in absolute degrees) of the copolymer, tg1 is the glass temperature of the homopolymer of monomer-1 whose mole fraction in the copolymer is M1, etc. Glass temperatures have been reported in the chemical literature for all of the common homopolymers.
The calculated Tg affords a first approximation of MFT, which can then be confirmed and refined by simple experiment if desired.
In general, If the MFT is substantially greater than room temperature, the result is not a continuous film, but instead is a powdery deposit, which is unsuitable as a coating for medical devices. However, if one is very careful, it may be possible to apply the base coat and then quickly place it in an oven heated to a temperature above the MFT, and still obtain a usable film. But the preferred method is to use a material having an MFT less,than the drying and curing temperature, because the latter method will consistently yield superior results, and does not depend so much on the agility of the laboratory worker.
The emulsion polymer that has been defined above will function as the base coat, or tie-coat, in a bilaminar coating, the top-coat being a hydrophilic material as will be defined later. The base coat will normally be formulated with a polyfunctional crosslinking agent, such as a polyaziridine, when an acid-functional emulsion polymer is used, which will not only insolubilize the base coat, but will also react with the top-coat at the interface and tie the two coats together with chemical bonds. As a matter of choice, the top-coat formulation may also include a crosslinking agent.
In the special cases where a polysaccharide or other hydroxylic material is a selected component of the top-coat, the functional group in the base coat may also be selected as a hydroxylic monomer, such as hydroxyethyl methacrylate, instead of or in addition to acidic monomer, and the grafting agent then can be a polyfunctional blocked isocyanate or dispersion of a water-insoluble polyisocyanate.
The following examples will illustrate and substantiate the principles described above, but should not be construed to limit the scope of the invention, beyond the limits set forth above.